Ischemic heart disease is the leading cause of death worldwide. Innate cardioprotective mechanisms influence the susceptibility of the myocardium to ischemia-reperfusion, the specific molecular mechanisms underlying susceptibility of the myocardium to ischemia-reperfusion (I-R) injury remain unclear. Indeed, the importance of understanding the underlying mechanisms responsible for ischemic heart disease was highlighted by the recently convened NHLBI Working Group on the Translation of Therapies for Protecting the Heart which recognized in their report that fundamental gaps in knowledge remain that limit the effective translation of cardioprotective therapies from experimental to clinical settings. Our understanding of the mechanisms responsible for cardiovascular protection has expanded tremendously, identifying a number of variables and pathways that influence the susceptibility of the myocardium to ischemic damage. One such recently recognized cardiovascular protective protein is ectonucleoside triphosphate diphosphohydrolase 1 (CD39). CD39 is uniquely positioned to be a key mediator of both thrombosis and myocardial ischemia-reperfusion injury. Overexpression of CD39 decreases thrombotic burden in a model of venous thrombosis and knockout of CD39 results in an increased infarct size in comparison to wild-type animals as well as loss of the innate cardioprotection afforded by the phenomenon of ischemic preconditioning. Therefore, the PI hypothesizes that targeted delivery of CD39 to sites of cardiovascular injury will attenuate in vivo arterial thrombosis and reduce myocardial ischemia/reperfusion injury. This project will define the role of CD39 in arterial thrombosis and myocardial ischemia/reperfusion injury and address whether targeted delivery of a cardiovascular protective protein via platelet-specific expression can reduce arterial thrombosis and myocardial ischemia-reperfusion injury. PUBLIC HEALTH RELEVANCE: The importance of understanding the underlying mechanisms responsible for ischemic heart disease, a leading cause of morbidity and mortality in the United States, was highlighted by the recently convened NHLBI Working Group on the Translation of Therapies for Protecting the Heart which recognized in their report that fundamental gaps in knowledge remain that limit the effective translation of cardioprotective therapies from experimental to clinical settings. CD39 (ectonucleoside triphosphate diphosphohydrolase 1) is uniquely positioned to be a key mediator of both thrombosis and myocardial ischemia-reperfusion injury. This project will define the role of CD39 in arterial thrombosis and myocardial ischemia/reperfusion injury and address whether targeted delivery of a cardiovascular protective protein via platelet-specific expression can reduce arterial thrombosis and myocardial ischemia-reperfusion injury.